The innate immune response to virus infection or protein aggregation in the brain has been implicated in the development of non-lymphocyte mediated neurological disorders such HIV-associated dementia (HAD), Alzheimer's disease. Increased expression of the proinflammatory cytokine TNFalpha and chemokine MCP-1 is often associated with clinical disease in HAD and AIzheimer's disease. Additionally, genetic polymorphism analysis linked high expression alleles of both TNFalpha and MCP-1 with increased risk for HAD. However, the mechanism by which these proteins contribute pathogenesis is not clear. Furthermore, it is unknown why TNFalpha and MCP-1 are upregulated in response to retrovirus infection. The current proposal will analyze the mechanism by which TNFalpha and MCP-1 contribute to neurological disease pathogenesis using a mouse model of retrovirus infection. Knockout mouse studies demonstrated that both TNFalpha and CCR2, the primary receptor for MCP-1, contribute to neurological disease in this model. In this proposal, we will determine if deficiency in either TNFalpha or CCR2 prevents the activation of other components of the innate immune response such as astrocyte or microglia activation and the induction of proinflammatory cytokine/chemokine responses. Additionally, we will also analyze the role of Toll-like receptors(TLR) in the induction of the cytokine/chemokine response to retrovirus infection in the brain. Initial studies indicate that TLR7, but not TLR3, is upregulated by neurovirulent virus infection in the brain. Thus, activation of the TLR7 pathway may induce the proinfiammatory cytokine/chemokine response associated with neurological disease. These studies how proinflammatory cytokines and chemokines are involved in non-inflammatory neurological diseases, leading the way for potential therapeutics that can inhibit entire pathways of activation, rather than trying to block soluble cytokines or chemokines.